Despite the fact that vascular head pain including migraine and cluster headache afflicts up to 15% of the population and inflicts significant suffering and economic loss, its pathophysiology and mechanism of treatment remain obscure. We have observed that 5-HT1B/D agonists useful in the treatment of vascular headaches significantly reduce trigeminal stimulation evoked plasma protein extravasation within dura mater of experimental rats and guinea pigs, as well as decrease c-fos expression within trigeminal nucleus caudalis (TNC) in guinea pigs following chemical stimulation of small diameter meningeal afferent fibers. These receptors appear to mediate prejunctional inhibition of neuropeptide release and possibly blockade of neurotransmission. Preliminary data indicate that valproic acid, a drug which inhibits GABA aminotransferase and which has been effective in migraine prophylaxis, blocks plasma protein extravasation and c-fos expression in the above models. Here we propose four specific aims to further characterize the identity and location of the GABA and 5-HT receptors relevant to the blockade of neurogenic inflammation. Initially we propose to extend preliminary data to determine the relevant GABA and serotonin receptor subtype. Secondly we propose receptor autoradiographic studies to determine whether these subtypes are expressed on trigeminal ganglia and trigeminal axons projecting to the meninges and/or on meningeal blood vessels. e also propose in situ hybridization studies to determine whether mRNA's encoding GABA receptor subtypes are expressed within trigeminal ganglia neurons. To test the hypothesis that agonists at 5-HT and GABA receptor subtypes inhibit release of neuropeptides from dural meningeal afferents, a third series of experiments will employ microdialysis techniques to measure neuropeptide levels within plasma taken from sagittal sinus and external jugular vein before, during and after trigeminal activation. Finally, we propose to test the hypothesis that selective agonists at the identified GABA and 5-HT receptor subtypes reduce the expression of c-fos antigen within TNC using immunohistochemistry. With these proposed experiments we seek to better understand the receptor pharmacology of vascular headaches to thereby establish a more rational basis for new drug discovery in migraine and cluster headache.